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SAPCD2 promotes neuroblastoma progression by altering the subcellular distribution of E2F7
Zi-Mu Zhang1, Hai-Bo Cao1,2, Zhi-Heng Li1
1Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215003, Jiangsu, China.
Abstract:
Recent studies uncovered the emerging roles of SAPCD2 (suppressor anaphase-promoting complex domain containing 2) in several types of human cancer. However, the functions and underlying mechanisms of SAPCD2 in the progression of neuroblastoma (NB) remain elusive. Herein, through integrative analysis of public datasets and regulatory network of GSK-J4, a small-molecule drug with anti-NB activity, we identified SAPCD2 as an appealing target with a high connection to poor prognosis in NB. SAPCD2 promoted NB progression in vitro and in vivo. Mechanistically, SAPCD2 could directly bind to cytoplasmic E2F7 but not E2F1, alter the subcellular distribution of E2F7 and regulate E2F activity. Among the E2F family members, the roles of E2F7 in NB are poorly understood. We found that an increasing level of nuclear E2F7 was induced by SAPCD2 knockdown, thereby affecting the expression of genes involved in the cell cycle and chromosome instability. In addition, Selinexor (KTP-330), a clinically available inhibitor of exportin 1 (XPO1), could induce nuclear accumulation of E2F7 and suppress the growth of NB. Overall, our studies suggested a previously unrecognized role of SAPCD2 in the E2F signaling pathway and a potential therapeutic approach for NB, as well as clues for understanding the differences in subcellular distribution of E2F1 and E2F7 during their nucleocytoplasmic shuttling.
Insights
Suppressor anaphase-promoting complex domain containing 2 (SAPCD2) drives neuroblastoma progression by regulating E2F7 nuclear localization. Targeting SAPCD2 or exportin 1 offers a potential therapeutic strategy for neuroblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Emerging evidence highlights the role of SAPCD2 in various cancers.
- The specific functions and mechanisms of SAPCD2 in neuroblastoma (NB) progression are not well understood.
- E2F7's role in NB remains largely unexplored.
Purpose of the Study:
- To investigate the role of SAPCD2 in neuroblastoma progression.
- To elucidate the underlying molecular mechanisms of SAPCD2 in NB.
- To identify potential therapeutic targets for NB.
Main Methods:
- Integrative analysis of public datasets and regulatory networks.
- In vitro and in vivo experiments to assess SAPCD2's function in NB.
- Analysis of protein-protein interactions and subcellular localization.
- Gene expression analysis related to cell cycle and chromosome instability.
Main Results:
- SAPCD2 was identified as a target linked to poor prognosis in NB and promoted NB progression.
- SAPCD2 directly binds to cytoplasmic E2F7, altering its subcellular distribution and regulating E2F activity.
- SAPCD2 knockdown led to increased nuclear E2F7, impacting cell cycle and chromosome instability genes.
- Selinexor (XPO1 inhibitor) induced nuclear E2F7 accumulation and suppressed NB growth.
Conclusions:
- SAPCD2 plays a significant role in NB progression through the E2F signaling pathway.
- SAPCD2 represents a potential therapeutic target for neuroblastoma.
- Understanding E2F7's nucleocytoplasmic shuttling provides insights into NB pathogenesis and treatment.
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